CN115960147A - Preparation method of azfudine and intermediate thereof - Google Patents
Preparation method of azfudine and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a method for preparing azfudine and an intermediate thereof. The invention provides a preparation method of a compound shown as a formula IX, which comprises the following steps: in a solvent, under the action of inorganic salt, a phase transfer catalyst and m-chloroperoxybenzoic acid, a compound shown as a formula VIII and m-chloroperbenzoic acid are subjected to a reaction shown as the following, and crystallization is carried out to obtain a compound shown as a formula IX. The preparation method provided by the invention avoids toxic and harmful and/or dangerous reagents and harsh reaction conditions in the GMP step, remarkably improves the total yield, remarkably improves the reaction repeatability and the amplifiable property, and is more suitable for industrial synthesis.
Description
Technical Field
The application belongs to the field of drug synthesis processes, and particularly relates to a preparation method of azlodine and an intermediate thereof.
Background
Azvudine (Azvudine), chemical name: 1- (4-azido-2-deoxy-2-fluoro-beta-D-ribofuranosyl) cytosine, which is a nucleoside reverse transcriptase inhibitor, can be used for treating AIDS and novel coronavirus infection. The molecular formula is as follows:
at present, the synthesis methods of the azvudine mainly comprise the following steps:
smith DB, et al, the design, synthesis, and anti activity of 4 '-azidocytidineacogens against C virus reproduction, the discovery of 4' -azidoabanecytidine, J Med chem, 2009;52 219-223, a method for synthesizing 2,2' -uridine epoxide by dehydration reaction with 4' -azido-uridine as a raw material is reported, then 2-fluorouridine is obtained by fluorination, and then the final product azvudine is obtained by chlorination and ammonolysis of phosphorus oxychloride, and another method for synthesizing is also reported by the authors in the article, wherein 4' -azido-uridine is synthesized by using 2-fluorouridine as a raw material, 4-imidazolyl nucleoside is obtained by substitution of one-pot method with phosphorus oxychloride chloroimidazole, and the final product is obtained by ammonolysis. In the ammonolysis process, protecting groups also need to be removed, and reagents such as phosphorus oxychloride and the like which cause serious pollution are used in the reaction process.
CN101177442A reports that 4' -azido uracil nucleoside is obtained by multi-step reaction of fluoro sugar, and then is subjected to chlorination and ammonolysis, and protective groups are removed simultaneously. Compared with the previous method, the reaction process is simpler, phosphorus oxychloride with serious pollution is used, a silver reagent is used in the penultimate step, so that the cost is higher, ag heavy metal is easily introduced, the refining of a final product is complicated, the yield is lower, and the method is not suitable for large-scale industrial production.
CN114149475A reports that 4' -azido uracil nucleoside is subjected to deprotection (ammonolysis or alcoholysis) and then reacts with hexamethyl silazane and acetamide to prepare the azvudine, and the method is simple to operate and low in yield, and the total yield of two steps is as follows: 42 to 54 percent.
Disclosure of Invention
The invention aims to solve the technical problems of low total yield, use of toxic and harmful hazardous or expensive reagents, harsh reaction conditions and/or poor reaction repeatability, scalability and the like of the existing preparation method of the azvudine, and provides a preparation method of the azvudine and an intermediate thereof, which are not suitable for large-scale synthesis. Compared with the existing preparation method, the preparation method provided by the invention avoids toxic and harmful and/or dangerous reagents and harsh reaction conditions in a GMP step, remarkably improves the total yield, remarkably improves the reaction repeatability and the amplifiability, and is more suitable for industrial synthesis.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a preparation method of a compound shown as a formula IX, which comprises the following steps: in a solvent, under the action of inorganic salt, a phase transfer catalyst and m-chloroperoxybenzoic acid, carrying out the following reaction on a compound shown as a formula VIII and m-chloroperbenzoic acid, and crystallizing to obtain a compound shown as a formula IX;
wherein R is a Is benzoyl or trifluoroacetyl.
The conditions for the preparation of the compound of formula IX may be those conventional in such reactions in the art. The following conditions are preferred in the present invention: the solvent may be a mixed solvent of water and a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent can be one or more of DCM (dichloromethane), DCE (1, 2-dichloroethane) and chloroform. Wherein, in the mixed solvent of water and halogenated hydrocarbon solvent, the volume ratio of water to halogenated hydrocarbon solvent can be 10-3: 5, e.g. 4:5. the amount of the solvent is such that the reaction is not affected.
The inorganic salt may be one or more of phosphate, dihydrogen phosphate and dihydrogen phosphate, preferably dihydrogen phosphate and more preferably disodium hydrogen phosphate.
The phase transfer catalyst may be tetrabutylammonium hydrogen sulfate.
The molar ratio of the inorganic salt to the compound of formula VIII can be 2 to 6:1, e.g. 4:1. the inorganic salts may be added in portions, for example in two portions, e.g. 0.4 to 0.6 equivalent of the total amount of inorganic salts added in the first portion, the remaining amount added in the second portion.
The molar ratio of the phase transfer catalyst to the compound of formula VIII can be 1 to 2:1, e.g. 1.35:1.
the molar ratio of the m-chlorobenzoic acid to the compound of formula VIII may be 1 to 2:1, e.g. 1.1:1.
the molar ratio of the m-chloroperoxybenzoic acid to the compound shown in the formula VIII can be 2-8: 1, e.g., 6:1. the m-chloroperoxybenzoic acid can be added in batches, for example, in two batches, for example, the equivalent weight of the m-chloroperoxybenzoic acid added in the first batch is 0.5-0.8 time of the total amount of the m-chloroperoxybenzoic acid added in the first batch, and the residual amount added in the second batch.
The temperature of the reaction may be 20 to 30 ℃.
The reaction time can be conventional in the field, and the reaction is completed only by ensuring that the product is not generated any more.
The compound of formula IX preferably comprises the following steps: adding a first part of m-chloroperoxybenzoic acid into a mixture of a solvent, a first part of inorganic salt, a phase transfer catalyst, a compound shown as a formula VIII and m-chloroperbenzoic acid in batches under the condition of temperature control for reaction, and adding a second part of inorganic salt and a second part of m-chloroperoxybenzoic acid again after the temperature control reaction for carrying out the reaction. Wherein, the temperature control preferably means that the temperature is controlled to be 20-30 ℃. The first portion of inorganic salts is preferably 0.4 to 0.6 equivalent of the total amount of inorganic salts. The first part of the m-chloroperoxybenzoic acid is preferably 0.5 to 0.8 equivalent of the total amount of the chloroperoxybenzoic acid.
The solvent for crystallization can be an alkane solvent, and the alkane solvent can be n-heptane.
The temperature of the crystallization can be 20-30 ℃.
The reaction may also include post-treatment after the reaction is completed. The post-treatment preferably comprises the steps of: quenching the reaction solution after the reaction is finished with a sodium sulfite solution (for example, an 18% sodium sulfite solution), carrying out solid-liquid separation (for example, filtration), washing the filter cake with a chlorinated hydrocarbon solvent (for example, dichloromethane), standing and separating the filtrate, adjusting the pH of the organic phase to 8-9 (for example, adjusting the pH of the organic phase with sodium carbonate), separating the liquid, washing the organic phase with a sodium bicarbonate solution (for example, a 5% sodium bicarbonate solution) (for example, 3 times), washing with water, and concentrating the organic phase to remove part of the solvent to obtain the compound concentrated solution shown in the formula IX.
The crystallization is preferably performed on the concentrated solution of the compound shown as the formula IX. Wherein the volume ratio of the concentrated solution to the crystallization solvent can be 1. And (4) performing solid-liquid separation after crystallization, and performing vacuum drying on a filter cake to obtain a compound product shown in the formula IX.
The invention provides a preparation method of azlodine, which comprises the following steps:
in a solvent, the compound represented by the formula IX, which is obtained according to the aforementioned method for preparing the compound represented by the formula IX, and ammonia gas are subjected to the following reaction to obtain azvudine;
the R is a Is benzoyl or trifluoroacetyl.
The conditions of the process for the preparation of said azvudine may be those conventional in the art for such reactions, and the following conditions are preferred in the present invention:
the reaction temperature is 20-30 ℃.
The reaction time can be conventional in the art, and the reaction is complete, wherein the reaction is finished under the condition that a product is not generated any more.
After the reaction is finished, post-treatment can be further included. The post-treatment may comprise the steps of: removing the solvent under reduced pressure, adding water, washing with water phase ethyl acetate, concentrating the water phase under reduced pressure, and filtering to obtain the azvudine.
In one embodiment, the method for preparing the compound represented by the formula IX further comprises the method for preparing the compound represented by the formula VIII, which comprises the following steps: in a solvent, under the action of alkali, carrying out the following reaction on a compound shown as a formula VII and an amino protection reagent to obtain a compound shown as a formula VIII;
wherein the amino protecting reagent is benzoyl chloride, benzoic anhydride, trifluoroacetyl chloride or trifluoroacetic anhydride, wherein R is a Is benzoyl or trifluoroacetyl.
The conditions for the preparation process of the compound represented by formula VIII may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:
the solvent may be a haloalkane solvent, such as DCM, DCE or chloroform. The amount of the solvent is such that the reaction is not affected.
The base may be an organic base such as pyridine, triethylamine or diisopropylamine.
The molar ratio of the base to the compound of formula VII may be 2 to 5:1, e.g. 4:1.
the mol ratio of the compound shown in the formula VII to the amino protective reagent can be 1.5-3: 1, e.g. 2:1.
the reaction may also comprise DMAP (4-dimethylaminopyridine). The molar ratio of the DMAP to the compound of formula VII may be 1:5 to 20, such as 1:10.
the temperature of the reaction may be-5-5 ℃.
The reaction time can be conventional in the art, and the reaction is complete, wherein the reaction is finished under the condition that a product is not generated any more.
After the reaction is finished, post-treatment can be further included. The post-treatment may comprise the steps of: adding dichloromethane into the reaction solution after the reaction is finished, adjusting the pH value to 6-7 (for example, adjusting the pH value by 0.2N hydrochloric acid), separating, washing the organic phase with water, washing with sodium bicarbonate solution (for example, saturated sodium bicarbonate solution) and washing with water in sequence, and concentrating the obtained organic phase to remove part of the solvent to obtain the compound concentrated solution shown in the formula VIII.
Crystallization may also be included after the reaction is complete. The solvent for crystallization can be an aromatic hydrocarbon solvent, and the aromatic hydrocarbon solvent can be toluene. The temperature of the crystallization can be 20-30 ℃. The crystallization is preferably performed by crystallizing the compound shown in the formula VIII from a concentrated solution. And (3) performing solid-liquid separation after crystallization, and drying a filter cake under reduced pressure to obtain a compound product shown in the formula VIII.
In one embodiment, the method for preparing the compound represented by formula IX may further comprise a method for preparing the compound VII, which comprises the steps of: in a solvent, reacting a compound shown as a formula VI with sodium azide and iodine chloride as shown in the specification to obtain a compound shown as a formula VII;
the conditions for the preparation process of the compound represented by formula VII may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:
the solvent may be an ether solvent, such as tetrahydrofuran. The amount of the solvent is such that the reaction is not affected. The solvent is generally controlled to have a moisture content of not higher than 0.10%. If the moisture content in the solvent is higher than 0.10%, the solvent needs to be repeatedly concentrated to control the moisture content to be not higher than 0.10%.
The molar ratio of the sodium azide to the compound of formula VI may be 1 to 3:1, e.g. 2.5:1.
the molar ratio of the iodine chloride to the compound of formula VI may be 1 to 2:1, e.g. 1.7:1.
the molar ratio of the iodine chloride to the sodium azide is 5.
The reaction time can be conventional in the field, and the reaction is completed only by ensuring that the product is not generated any more.
The temperature of the reaction may be-5-5 ℃.
The reaction was monitored by TLC for completion, and if not completed, sodium azide and iodine chloride were added until the reaction was complete.
After the reaction is finished, post-treatment can be further included; the post-treatment may comprise the steps of: quenching with sodium thiosulfate solution (such as 20% sodium thiosulfate), extracting with ethyl acetate, washing the organic phase with saturated sodium chloride solution, concentrating under reduced pressure, adding dichloromethane twice, and concentrating under reduced pressure to obtain concentrated solution of compound shown in formula VII.
Crystallization may also be included after the reaction is complete. The solvent for crystallization can be an alkane solvent, and the alkane solvent can be n-heptane. The temperature of the crystallization can be 0-10 ℃. The crystallization is preferably performed by crystallizing the compound concentrate shown in the formula VII. And (4) performing solid-liquid separation after crystallization, and performing vacuum drying on a filter cake to obtain a compound product shown in the formula VII.
In one embodiment, the method for preparing the compound represented by formula IX may further comprise a method for preparing the compound VI, which comprises the following steps: reacting a compound shown as a formula V with sodium methoxide in a solvent to obtain a compound shown as a formula VI;
the conditions for the preparation process of the compound represented by formula VI may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:
the solvent may be an alcohol solvent or an ether solvent, such as methanol or tetrahydrofuran. The amount of the solvent is such that the reaction is not affected.
The molar ratio of the sodium methoxide to the compound of formula V may be 2 to 5:1, e.g. 3.5:1.
the temperature of the reaction may be 0-10 ℃.
The reaction time can be conventional in the field, and the reaction is completed only by ensuring that the product is not generated any more.
After the reaction is finished, post-treatment can be further included; the post-treatment may comprise the steps of: adding water into the reaction solution after the reaction is finished, concentrating under reduced pressure, filtering, washing filter cake water, extracting filtrate with ethyl acetate, adjusting the pH of the water phase to 7-8 (for example, adjusting the pH by sodium bisulfite), extracting with ethyl acetate, and concentrating the organic phase to remove the solvent to obtain the compound shown in the formula VI.
In one embodiment, the method for preparing the compound represented by formula IX may further comprise a method for preparing the compound V, which comprises the following steps: in a solvent, carrying out a reaction shown as the following on a compound shown as a formula IV, imidazole, triphenylphosphine and iodine to obtain a compound shown as a formula V;
the conditions of the preparation method of the compound represented by the formula V may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:
the solvent may be an ethereal solvent, such as tetrahydrofuran, e.g., anhydrous tetrahydrofuran. The amount of the solvent is such that the reaction is not affected.
The molar ratio of the imidazole to the compound of formula IV may be 1 to 3:1, e.g. 2:1.
the molar ratio of the triphenyl phosphine to the compound shown in the formula IV can be 1-3: 1, e.g. 1.5:1.
the molar ratio of the iodine to the compound of formula IV may be 1 to 3:1, e.g. 1.5:1.
the temperature of the reaction may be 20-30 ℃.
The reaction time can be conventional in the art, and the reaction is complete, wherein the reaction is finished under the condition that a product is not generated any more.
The reaction may also include post-treatment after the reaction is completed. The post-treatment may comprise the steps of: quenching with sodium sulfite solution (such as 5% sodium sulfite solution), concentrating under reduced pressure, extracting with ethyl acetate, and concentrating the organic phase under reduced pressure to obtain a concentrated solution of the compound of formula V.
Wherein, the reaction can also comprise crystallization after the reaction is finished. The solvent for crystallization can be an ester solvent, and the ester solvent can be ethyl acetate. The crystallization temperature may be 0 to 10 ℃. The crystallization is preferably performed by crystallizing the compound shown in the formula V from a concentrated solution. And (3) carrying out solid-liquid separation after crystallization, and carrying out vacuum drying on a filter cake to obtain a compound product shown in the formula V.
In one embodiment, the method for preparing the compound represented by formula IX may further comprise a method for preparing the compound IV, comprising the steps of: reacting the compound shown in the formula III with an ammonia-methanol solution to obtain a compound shown in the formula IV;
wherein R is a Is benzoyl or trifluoroacetyl.
The conditions of the preparation method of the compound represented by the formula IV can be the conditions conventional in such reactions in the field, and the following conditions are preferred in the invention:
the concentration of the ammonia-methanol solution may be 7mol/L.
The temperature of the reaction may be 25-35 ℃.
The reaction time can be conventional in the art, and the reaction is complete, wherein the reaction is finished under the condition that a product is not generated any more.
When R is a In the case of benzoyl, the reaction time may be 50 to 60 hours.
When R is a In the case of trifluoroacetyl, the reaction time may be 15 to 20 hours.
After the reaction is finished, post-treatment can be further included. The post-treatment may comprise the steps of: and (3) controlling the temperature of the reaction liquid after the reaction to be 40-50 ℃, decompressing and concentrating to be dry, mixing with an alcohol solvent (such as methanol), cooling to be 25-35 ℃, then mixing with a halogenated alkane solvent (such as dichloromethane), controlling the temperature to be 0-10 ℃, stirring (such as 2-4 hours), carrying out solid-liquid separation, and carrying out vacuum drying on a filter cake to obtain the compound shown in the formula IV.
In a certain embodiment, the preparation method of the compound represented by formula IX may further include a preparation method of the compound III, which includes the following steps:
(1) The amino group R a Reacting the protected cytosine, hexamethyldisilazane and ammonium sulfate; obtaining a mixture;
(2) In a solvent, reacting a compound shown as a formula II with the mixture obtained in the step (1) to obtain a compound shown as a formula III;
wherein, R is a Is benzoyl or trifluoroacetyl.
The conditions of the process for the preparation of the compound of formula III may be those conventional in the art for such reactions. The following conditions are preferred in the present invention:
in the step (1), the amino group R a The molar ratio of protected cytosine to said compound of formula IV may be from 1 to 3:1, e.g. 2:1.
in the step (1), the molar ratio of the hexamethyldisilazane to the compound represented by the formula IV may be 10 to 20:1, e.g. 14:1.
in the step (1), the molar ratio of the ammonium sulfate to the compound shown in the formula IV can be 1-2: 1, e.g. 1.3:1.
in the step (1), the reaction temperature is 130-140 ℃.
In the step (2), the solvent may be a halogenated hydrocarbon solvent, for example, methylene chloride.
In the step (2), the reaction temperature is 65-75 ℃.
The reaction time can be conventional in the field, and the reaction is completed only by ensuring that the product is not generated any more.
The reaction may also include post-treatment after the reaction is completed. The post-treatment may comprise the steps of: cooling to 0-10 deg.C, adding water (stirring at 20-30 deg.C for 4-10 hr), filtering, washing with organic phase water, concentrating under reduced pressure, and crystallizing with alkane solvent (such as n-heptane) to obtain compound shown in formula III.
In one embodiment, the method for preparing the compound represented by formula IX may further comprise a method for preparing the compound II, which comprises the following steps: in a solvent, reacting a compound shown as a formula I with a hydrogen bromide-glacial acetic acid solution to obtain a compound shown as a formula II;
the conditions of the preparation method of the compound shown in the formula II can be the conditions conventional in such reactions in the field, and the following conditions are preferred in the invention:
the solvent may be a halogenated hydrocarbon solvent, such as methylene chloride.
The concentration of the hydrogen bromide-glacial acetic acid solution is 33% (mass percentage concentration).
The temperature of the reaction is 15-25 ℃.
The reaction time can be conventional in the art, and the reaction is complete, wherein the reaction is finished under the condition that a product is not generated any more.
The reaction may also include post-treatment after the reaction is completed. The post-treatment may comprise the steps of: adding water, separating, washing the organic phase with water, adjusting pH to 7 or higher (such as adjusting with 5% sodium bicarbonate), and removing solvent from the organic phase to obtain the compound shown in formula II.
The obtained compound represented by the formula II can be directly used for preparing the compound represented by the formula III without further purification.
The invention provides a preparation method of azlodine, which comprises the following steps:
wherein R is a Is benzoyl or trifluoroacetyl;
the operation and conditions of each step of the reaction in the preparation method can be the same as those of the corresponding reaction in any scheme of the invention.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method provided by the invention avoids toxic and harmful and/or dangerous reagents and harsh reaction conditions, remarkably improves the total yield, remarkably improves the reaction repeatability and the scalability, and is more suitable for industrial synthesis.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
Example 1: synthesis of Compound III
300g of the compound I and 3L of dichloromethane were added into the reaction kettle 1 while stirring, the temperature was controlled at 15 to 25 ℃, and 840g of 33% hydrogen bromide-glacial acetic acid solution was added dropwise. After the dropwise addition, the reaction is carried out for 14 to 18 hours under the condition of heat preservation. After the reaction is finished, 3L of water is dropwise added at controlled temperature, standing and liquid separation are carried out, the organic phase is washed by 33L of water, the organic phase is neutralized by 5% sodium bicarbonate until the pH value is more than or equal to 7, liquid separation is carried out, and the organic phase is concentrated until no liquid flows out, so that the compound II is obtained.
Amino-protected cytosine (1.29mol, 2.0 eq.), 900g hexamethyldisilazane and 69g ammonium sulfate were added to reaction vessel 2, and the temperature was raised to 130-140 ℃ for 10 hours.
Adding 15L of chloroform into a reaction kettle 1, stirring to obtain a uniform solution, transferring the obtained solution into a reaction kettle 2, heating the reaction kettle to 65-75 ℃, and carrying out heat preservation reaction for 16 hours. The temperature is reduced to 0-10 ℃, and 1.5L of water is slowly dropped. After the dripping is finished, slowly raising the temperature to 20-30 ℃, and keeping the temperature and stirring for 4-10 hours. The filtrate was filtered, the filtrate was separated and the organic layer was washed with 1.5L of water. Concentrating the organic phase under reduced pressure to 0.6-0.9L, controlling the temperature at 20-30 deg.C, and adding 3L n-heptane dropwise. After the dripping is finished, stirring for 2-3 hours at controlled temperature. Filtering, rinsing the filter cake with n-heptane, and vacuum drying to obtain off-white solid compound III.
R a In the case of a benzoyl group, the yield was 92.3%, MS:558.0 (M + H) + )，
R a In the case of trifluoroacetyl group, the yield is 88.4%, and MS:549.9 (M + H) + )。
Example 2: synthesis of Compound IV
100g of compound III and 1L of ammonia-methanol solution (7 mol/L) are added into a reaction kettle, and the temperature is controlled to be 25-35 ℃ for reaction. After the reaction is complete (R) a Reacting for 50-60 hours when the benzoyl is benzene formyl; r is a Reacting for 15-20 hours when the acetyl is trifluoroacetyl), controlling the temperature to be 40-50 ℃, and concentrating under reduced pressure until the acetyl is dry. 100mL of methanol was added to the reaction vessel, stirred until dissolved, cooled to 25-35 ℃ and 1L of dichloromethane was added dropwise. After the dripping is finished, the temperature is reduced to 0 to 10 ℃, and the mixture is kept and stirred for 2 to 4 hours. Filtering, washing the filter cake with dichloromethane, and vacuum drying to obtain off-white solid compound IV. MS 245.9 (M + H) + ) Molar yield 93.2% (R) a = benzoyl), 93.4% (R) a = trifluoroacetyl group).
Example 3: synthesis of Compound V
100g of compound IV,55.3g of imidazole (2.0 equivalents), 160g of triphenylphosphine (1.5 equivalents) and 500mL of anhydrous tetrahydrofuran are added to the reaction vessel and the temperature is adjusted to 20-30 ℃. A solution of 155g of iodine (1.5 eq) in 500mL of tetrahydrofuran was added dropwise to the kettle, with the temperature controlled at 20-30 ℃. After the dropwise addition, the reaction is carried out for 3 to 5 hours under the condition of heat preservation. Quenching with 5% sodium sulfite solution, and concentrating under reduced pressure to 900-1100mL. Extracting with ethyl acetate (500mL. Times.3), concentrating the organic phase under reduced pressure to 400-500mL, cooling to 0-10 deg.C, and stirring for 2-3 hr. Filtration, cake rinsing with cold ethyl acetate, vacuum drying off white-like solid compound V,234g, ms(M+H + ) Content 51.0%, yield 82.3%.
Example 4: synthesis of Compound VII
The method comprises the following steps:
100g of compound V (net content) and 1L of methanol are added into a reaction kettle, and 53g of sodium methoxide is slowly added dropwise at the temperature of 0-10 ℃. After the addition, the temperature is controlled to be 0-10 ℃ for reaction for 14-16 hours. Slowly dripping 1L of water at the temperature of 0-10 ℃, concentrating under reduced pressure to 900-1000mL, filtering, and rinsing the filter cake with 200mL of water. The filtrate was extracted with ethyl acetate (500ml x 2) and the organic phase was discarded. The aqueous phase was adjusted to pH 7-8 with sodium bisulfite and extracted with ethyl acetate (500mL. Multidot.3), and the organic phase was washed with 500mL of saturated saline and concentrated to dryness to give Compound VI.
Then adding 1000mL of tetrahydrofuran, concentrating to 400-600mL, and detecting that the water content is not higher than 0.10%; if the water content is higher than 0.1%, repeatedly concentrating with tetrahydrofuran until the water content is not higher than 0.10%. Cooling to room temperature, and adding 47g of sodium azide into the reaction kettle; and cooled to-5-5 ℃. 78g of iodine chloride was slowly dropped under the temperature controlled at-5 to 5 ℃. After the dropwise addition, the reaction is kept for 1-2 hours, and the reaction is finished by TLC. And (3) if the reaction is not finished, adding sodium azide and iodine chloride (mass ratio: sodium azide: iodine chloride = 5). After completion of the reaction, quenched with 20% sodium thiosulfate and extracted with ethyl acetate (500ml × 3). The combined organic phases were washed with saturated sodium chloride solution (500ml × 2). The organic phase was concentrated under reduced pressure to about 200mL, 1000mL of methylene chloride was added, and concentrated under reduced pressure to about 200mL. 500mL of n-heptane is added dropwise while stirring, the temperature is reduced to 0-10 ℃, and the mixture is stirred for 2-3 hours under the condition of heat preservation. Filtering, rinsing the filter cake with n-heptane, vacuum drying at 30-40 deg.C to obtain 56.9g off-white solid compound VII, MS:396.8 (M + H) + ) The total yield of the two steps is 51.0%.
The second method comprises the following steps: 100g of compound V (net content) and 1L of tetrahydrofuran are added into a reaction kettle, and 53g of sodium methoxide is slowly added dropwise at the temperature of 0-10 ℃. After the addition, the temperature is controlled to be 0-10 ℃ for reaction for 14-16 hours. Slowly dripping 1L of water at the temperature of 0-10 ℃, concentrating under reduced pressure to 900-1000mL, filtering, and rinsing the filter cake with 200mL of water. The filtrate was extracted with ethyl acetate (500ml × 2) and the organic phase was discarded. The aqueous phase was adjusted to pH 7-8 with sodium bisulfite and extracted with ethyl acetate (500mL. Multidot.3), and the organic phase was washed with 500mL of saturated saline and concentrated to dryness to give Compound VI.
Then adding 1000mL of tetrahydrofuran, concentrating to 400-600mL, and detecting that the water content is not higher than 0.10%; if the water content is higher than 0.1%, repeatedly concentrating with tetrahydrofuran until the water content is not higher than 0.10%. Cooling to room temperature, and adding 47g of sodium azide into the reaction kettle; and cooled to-5-5 ℃. 78g of iodine chloride was slowly dropped under the temperature controlled at-5 to 5 ℃. After the dropwise addition, the reaction is carried out for 1-2 hours under the condition of heat preservation, and TLC shows that the reaction is finished. And if the reaction is not finished, adding sodium azide and iodine chloride (mass ratio: sodium azide: iodine chloride = 5). After completion of the reaction, quenched with 20% sodium thiosulfate and extracted with ethyl acetate (500ml × 3). The combined organic phases were washed with saturated sodium chloride solution (500ml × 2). The organic phase was concentrated under reduced pressure to about 200mL, 1000mL of methylene chloride was added, and concentrated under reduced pressure to about 200mL. 500mL of n-heptane is added dropwise while stirring, the temperature is reduced to 0-10 ℃, and the mixture is stirred for 2-3 hours under the condition of heat preservation. Filtering, rinsing filter cake with n-heptane, vacuum drying at 30-40 deg.C to obtain 85.0g off-white solid compound VII with two-step total molar yield of 76.2%.
Example 5: synthesis of Compound VIII
100g of compound VII,102g of triethylamine (4.0 eq), 3.11g of 4-dimethylaminopyridine and 1000mL of dichloromethane were added to the reaction vessel and cooled to-5-5 ℃. Controlling the temperature to be-5-5 ℃, and slowly dripping 2.0 equivalent of acyl chloride or anhydride. After the dropwise addition, the reaction is carried out for 1 to 2 hours under the condition of heat preservation. 1000mL of methylene chloride was added to the reaction kettle and the pH was adjusted to 6-7 with 0.2N hydrochloric acid. The organic phase was separated and washed with 500mL of water, 500mL of saturated sodium bicarbonate solution, and 500mL of water in this order. The organic phase was concentrated under reduced pressure to 800-900mL, 1000mL of toluene was added, and concentrated under reduced pressure to 900-1000mL. Cooling to 20-30 deg.C, stirring for 2-4 hr, filtering, rinsing the filter cake with 300mL of toluene, and drying under reduced pressure to obtain an off-white solid.
Molar yield: 85.1% (R) a = benzoyl), MS:604.8 (M + H) + )，
Molar yield: 82.0% (R) a = trifluoroacetyl), MS 588.8 (M + H) + )。
Example 6: synthesis of Compound IX
100g of compound VIII,400g of water, 500mL of dichloromethane, 2.2 equivalents of disodium hydrogenphosphate, 1.35 equivalents of tetrabutylammonium hydrogensulfate and 1.1 equivalents of m-chlorobenzoic acid are charged into the reaction vessel. The temperature is adjusted to 20 to 30 ℃, and 4.0eq of m-chloroperoxybenzoic acid is added in batches at the controlled temperature. After the addition, the temperature is controlled to be 20-30 ℃ and the mixture is stirred for 0.5 hour. Controlling the temperature to be 20-30 ℃, adding 1.9 equivalents of disodium hydrogen phosphate and adding 2.0 equivalents of m-chloroperoxybenzoic acid in batches. After the addition, the reaction is carried out for 15 to 16 hours under the condition of heat preservation. After completion of the reaction, it was quenched with 18% sodium sulfite solution, filtered and the filter cake was rinsed with dichloromethane. Standing the filtrate, separating, adjusting pH of the organic phase to 8-9 with sodium carbonate, and separating. The organic phase was washed with 5% sodium bicarbonate solution (500ml × 3) and 500mL water. Concentrating the organic phase to 200-300mL, cooling to 20-30 ℃, dropwise adding 800mL of n-heptane, stirring at the constant temperature, filtering, washing a filter cake with 200mL of n-heptane, and drying in vacuum to obtain a white solid compound IX.
The molar yield is as follows: 85.1% (R) a = benzoyl), MS 634.9 (M + H) + ) 98.5% purity (HPLC);
the molar yield is as follows: 79.2% (R) a = trifluoroacetyl), MS 618.9 (M + H) + ) Purity (HPLC) 98.2%.
Example 7: synthesis of azvudine
Adding 100g of compound IX and 500mL of methanol into a reaction kettle, adjusting the temperature to 20-30 ℃, controlling the temperature, introducing ammonia gas until the reaction is complete, and concentrating under reduced pressure until no liquid flows out. 500mL of water and 500mL of ethyl acetate were added, the temperature was raised to 35-45 deg.C, the layers were separated, the aqueous layer was washed with ethyl acetate (500mL. Multidot.2), and the combined organic layers were extracted with 300mL of water. Mixing the water phases, controlling the temperature to be not higher than 40 ℃, concentrating under reduced pressure to 0.5-1L, and filtering. The filter cake was rinsed with ethyl acetate to give a pale yellow solid.
Molar yield: 82.5% (R) a = benzoyl), purity (HPLC) 99.35%,
molar yield: 85.2% (R) a = trifluoroacetyl group), purity (HPLC) 99.42%,
MS:286.9(M+H + )。
Claims (10)
1. a method for preparing a compound shown as a formula IX, which is characterized by comprising the following steps: in a solvent, under the action of inorganic salt, a phase transfer catalyst and m-chloroperoxybenzoic acid, carrying out the following reaction on a compound shown as a formula VIII and m-chloroperbenzoic acid, and crystallizing to obtain a compound shown as a formula IX;
wherein R is a Is benzoyl or trifluoroacetyl.
2. A process for the preparation of a compound of formula IX according to claim 1, which satisfies one or more of the following conditions:
(1) The solvent is a mixed solvent of water and halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably one or more of DCM, DCE and chloroform; the volume ratio of the water to the halogenated hydrocarbon solvent is 10-3: 5, e.g., 4:5;
(2) The inorganic salt is one or more of phosphate, dihydrogen phosphate and dihydrogen phosphate, preferably dihydrogen phosphate and disodium hydrogen phosphate;
(3) The phase transfer catalyst is tetrabutylammonium hydrogen sulfate;
(4) The molar ratio of the inorganic salt to the compound shown in the formula VIII is 2-6: 1, e.g. 4:1; the inorganic salt is preferably added in batches, more preferably in two batches, wherein the equivalent weight of the inorganic salt added in the first batch is 0.4-0.6 time of the total weight of the inorganic salt added in the first batch, and the rest amount is added in the second batch;
(5) The molar ratio of the phase transfer catalyst to the compound shown in the formula VIII is 1-2: 1, e.g. 1.35:1;
(6) The mol ratio of the m-chlorobenzoic acid to the compound shown in the formula VIII is 1-2: 1, e.g. 1.1:1;
(7) The mol ratio of the m-chloroperoxybenzoic acid to the compound shown in the formula VIII is 2-8: 1, e.g., 6:1; the m-chloroperoxybenzoic acid is preferably added in batches, more preferably added in two batches, the equivalent weight of the m-chloroperoxybenzoic acid added in the first batch is 0.5-0.8 time of the total amount of the m-chloroperoxybenzoic acid, and the rest amount is added in the second batch;
(8) The reaction temperature is 20-30 ℃;
(9) The solvent for crystallization is an alkane solvent, preferably n-heptane; the crystallization temperature is 20-30 ℃; the crystallization is preferably performed on the compound concentrated solution shown as the formula IX; wherein the volume ratio of the concentrated solution to the crystallization solvent is 1.
3. The process for the preparation of a compound of formula IX according to claim 1 or 2, further comprising a process for the preparation of a compound of formula VIII comprising the steps of: in a solvent, under the action of alkali, carrying out the following reaction on a compound shown as a formula VII and an amino protection reagent to obtain a compound shown as a formula VIII;
wherein the amino protective reagent is benzoyl chloride, benzoic anhydride,Trifluoroacetyl chloride or trifluoroacetic anhydride, in which R is a Is benzoyl or trifluoroacetyl;
the reaction preferably satisfies one or more of the following conditions:
(1) The solvent is a haloalkane solvent, such as DCM, DCE or chloroform;
(2) The base is an organic base such as pyridine, triethylamine or diisopropylamine;
(3) The molar ratio of the base to the compound represented by the formula VII is 2-5: 1, e.g. 4:1;
(4) The molar ratio of the compound shown as the formula VII to the amino protective reagent is 1.5-3: 1, e.g. 2:1;
(5) The reaction further comprises DMAP; the molar ratio of the DMAP to the compound of formula VII is 1:5 to 20, for example 1:9 to 10 percent;
(6) The temperature of the reaction is-5-5 ℃.
4. A process for the preparation of a compound of formula IX according to claim 3, further comprising a process for the preparation of said compound VII, comprising the steps of: in a solvent, carrying out the following reaction on a compound shown as a formula VI, sodium azide and iodine chloride to obtain a compound shown as a formula VII;
the reaction preferably satisfies one or more of the following conditions:
(1) The solvent is an ether solvent such as tetrahydrofuran;
(2) The molar ratio of the sodium azide to the compound shown in the formula VI is 1-3: 1, for example, 2.4 to 2.6:1;
(3) The molar ratio of the iodine chloride to the compound shown in the formula VI is 1-2: 1, e.g., 1.6 to 1.8:1;
(4) The molar ratio of the iodine chloride to the sodium azide is 5;
(5) The temperature of the reaction is-5 to 5 ℃.
5. A process for the preparation of a compound of formula IX according to claim 4, further comprising a process for the preparation of said compound VI, comprising the steps of: reacting a compound shown as a formula V with sodium methoxide in a solvent to obtain a compound shown as a formula VI;
the reaction preferably satisfies one or more of the following conditions:
(1) The solvent is an alcohol solvent or an ether solvent, such as methanol or tetrahydrofuran;
(2) The molar ratio of the sodium methoxide to the compound shown in the formula V is 2-5: 1, e.g., 3.4 to 3.6:1;
(3) The temperature of the reaction is 0-10 ℃.
6. A process for the preparation of a compound of formula IX according to claim 5, further comprising a process for the preparation of said compound V, comprising the steps of: in a solvent, carrying out a reaction shown as the following on a compound shown as a formula IV, imidazole, triphenylphosphine and iodine to obtain a compound shown as a formula V;
the reaction preferably satisfies one or more of the following conditions:
(1) The solvent is an ether solvent such as tetrahydrofuran;
(2) The molar ratio of the imidazole to the compound shown in the formula IV is 1-3: 1, e.g. 2:1;
(3) The molar ratio of the triphenyl phosphine to the compound shown in the formula IV is 1-3: 1, e.g. 1.5:1;
(4) The molar ratio of the iodine to the compound shown in the formula IV is 1-3: 1, e.g. 1.5:1;
(5) The temperature of the reaction is 20-30 ℃.
7. The method of claim 6, further comprising a step of preparing said compound IV, comprising the steps of: carrying out the following reaction on the compound shown as the formula III and an ammonia-methanol solution to obtain a compound shown as a formula IV;
wherein R is a Is benzoyl or trifluoroacetyl;
the reaction preferably satisfies one or more of the following conditions:
(1) The concentration of the ammonia-methanol solution is 7mol/L;
(2) The reaction temperature is 25-35 ℃;
(3) When R is a When the benzoyl is adopted, the reaction time is 50-60 hours;
(4) When R is a In the case of trifluoroacetyl, the reaction time is 15 to 20 hours.
8. A process for the preparation of a compound of formula IX according to claim 7, further comprising a process for the preparation of said compound III, comprising the steps of:
(1) The amino group R a Reacting the protected cytosine, hexamethyldisilazane and ammonium sulfate; obtaining a mixture;
(2) In a solvent, carrying out a reaction shown as the following on a compound shown as a formula II and the mixture obtained in the step (1) to obtain a compound shown as a formula III;
wherein, R is a Is benzoyl or trifluoroacetyl;
the reaction preferably satisfies one or more of the following conditions:
(1) In the step (1), the amino group R a The molar ratio of protected cytosine to the compound of formula IV is from 1 to 3:1, e.g. 2:1;
(2) In the step (1), the molar ratio of the hexamethyldisilazane to the compound represented by the formula IV is 5-20: 1, for example 8 to 10:1;
(3) In the step (1), the molar ratio of the ammonium sulfate to the compound shown in the formula IV is 1-2: 1, for example 1.2 to 1.4:1;
(4) In the step (1), the reaction temperature is 130-140 ℃;
(5) In the step (2), the solvent is a halogenated hydrocarbon solvent, such as dichloromethane;
(6) In the step (2), the reaction temperature is 65-75 ℃.
9. A process for the preparation of a compound of formula IX according to claim 8, further comprising a process for the preparation of said compound II, comprising the steps of: in a solvent, carrying out a reaction shown as the following by a compound shown as a formula I and a hydrogen bromide-glacial acetic acid solution to obtain a compound shown as a formula II;
the reaction preferably satisfies one or more of the following conditions:
(1) The solvent is a halogenated hydrocarbon solvent such as dichloromethane;
(2) The concentration of the hydrogen bromide-glacial acetic acid solution is 33 percent;
(3) The temperature of the reaction is 15-25 ℃.
10. The preparation method of the azvudine is characterized by comprising the following steps: reacting a compound of formula IX, obtained by the process for preparing a compound of formula IX according to any one of claims 1 to 9, with ammonia in a solvent to obtain azvudine;
the R is a Is benzoyl or trifluoroacetyl;
the temperature of the reaction is preferably 20 to 30 ℃.
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